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For decades, basic research on the underlying mechanisms of nociception has held promise to translate into efficacious treatments for patients with pain. Despite great improvement in the understanding of pain physiology and pathophysiology, translation to novel, effective treatments for acute and chronic pain has however been limited, and they remain an unmet medical need. In this opinion paper bringing together pain researchers from very different disciplines, the opportunities and challenges of translational pain research are discussed. The many factors that may prevent the successful translation of bench observations into useful and effective clinical applications are reviewed, including interspecies differences, limited validity of currently available preclinical disease models of pain, and limitations of currently used methods to assess nociception and pain in non-human and human models of pain. Many paths are explored to address these issues, including the backward translation of observations made in patients and human volunteers into new disease models that are more clinically relevant, improved generalization by taking into account age and sex differences, and the integration of psychobiology into translational pain research. Finally, it is argued that preclinical and clinical stages of developing new treatments for pain can be improved by better preclinical models of pathological pain conditions alongside revised methods to assess treatment-induced effects on nociception in human and non-human animals. Significance: For decades, basic research of the underlying mechanisms of nociception has held promise to translate into efficacious treatments for patients with pain. Despite great improvement in the understanding of pain physiology and pathophysiology, translation to novel, effective treatments for acute and chronic pain has however been limited, and they remain an unmet medical need.
Learn More >The transcriptional repressor positive regulatory domain I-binding factor 1 (PRDM1) is expressed in adult mouse dorsal root ganglion and regulates the formation and function of peripheral sensory neurons. The authors hypothesized that PRDM1 in the dorsal root ganglion may contribute to peripheral nerve injury-induced nociception regulation and that its mechanism may involve Kv4.3 channel transcriptional repression.
Learn More >The nucleus accumbens (NAc) and the ventral tegmental area (VTA) are critical hubs in the brain circuitry controlling chronic pain. Yet, how these 2 regions interact to shape the chronic pain state is poorly understood. Our studies show that in mice, spared nerve injury (SNI) induced alterations in the functional connectome of D2-receptor expressing spiny projection neurons in the core region of the NAc-enhancing connections with prelimbic cortex and weakening them with basolateral amygdala. These changes, which were attributable in part to SNI-induced suppression of VTA dopaminergic signaling, were adaptive because mimicking them chemogenetically alleviated the anxiety and social withdrawal accompanying injury. By contrast, chemogenetic enhancement of activity in VTA dopaminergic neurons projecting to the medial shell of the NAc selectively suppressed tactile allodynia in SNI mice. These results suggest that SNI induces regionally specific alterations in VTA dopaminergic signaling in the NAc to promote environmental reengagement after injury. However, countervailing, homeostatic mechanisms limit these adaptive changes, potentially leading to the chronic pain state.
Learn More >Previous studies have demonstrated that the synaptic EphB1 receptor tyrosine kinase is a major mediator of neuropathic pain, suggesting that targeting the activity of this receptor might be a viable therapeutic option. Therefore, we set out to determine if any FDA-approved drugs can act as inhibitors of the EphB1 intracellular catalytic domain. An in silico screen was first used to identify a number of tetracycline antibiotics which demonstrated potential docking to the ATP-binding catalytic domain of EphB1. Kinase assays showed that demeclocycline, chlortetracycline, and minocycline inhibit EphB1 kinase activity at low micromolar concentrations. In addition, we cocrystallized chlortetracycline and EphB1 receptor, which confirmed its binding to the ATP-binding domain. Finally, in vivo administration of the three-tetracycline combination inhibited the phosphorylation of EphB1 in the brain, spinal cord, and dorsal root ganglion (DRG) and effectively blocked neuropathic pain in mice. These results indicate that demeclocycline, chlortetracycline, and minocycline can be repurposed for treatment of neuropathic pain and potentially for other indications that would benefit from inhibition of EphB1 receptor kinase activity.
Learn More >The clinical efficacy of migraine therapeutic agents directed towards the calcitonin-gene related peptide (CGRP) pathway has confirmed the key role of this axis in migraine pathogenesis. Three antibodies against CGRP – fremanezumab, galcanezumab and eptinezumab – and one antibody against the CGRP receptor, erenumab, are clinically approved therapeutics for the prevention of migraine. In addition, two small molecule CGRP receptor antagonists, ubrogepant and rimegepant, are approved for acute migraine treatment. Targeting either the CGRP ligand or receptor is efficacious for migraine treatment; however, a comparison of the mechanism of action of these therapeutic agents is lacking in the literature.
Learn More >Nitroglycerin administration allows the study of cluster headache attacks in their entirety in a standardised way.
Learn More >Appropriate outcome measures and high-quality intervention trials are critical to advancing care for children with chronic pain. Our aim was to update a core outcome set for pediatric chronic pain interventions. The first phase involved collecting providers', patients', and parents' perspectives about treatment of pediatric chronic pain to understand clinically meaningful outcomes to be routinely measured. The second phase was to reach consensus of mandatory and optional outcome domains following the OMERACT framework. A Modified Delphi study with two rounds was conducted including three stakeholder groups: children with chronic pain (n=93), their parents (n=90), and health care providers who treat youth with chronic pain (n=52). Quantitative and qualitative data from Round 1 of the Delphi study were summarized to identify important outcomes, which were condensed to a list of 10 outcome domains. Round 2 surveys were analyzed to determine the importance of the 10 domains and their relative ranking in each stakeholder group. A virtual consensus conference was held with the Steering committee to reach consensus on a set of recommended outcome domains for pediatric chronic pain clinical trials. It was determined, by unanimous vote, that Pain Severity, Pain Interference with Daily Living, Overall Well-being, and Adverse Events, including Death, would be considered Mandatory domains to be assessed in all trials of any type of intervention. Emotional Functioning, Physical Functioning, and Sleep were Important but optional domains. Last, the research agenda identifies several important emerging areas, including biomarkers. Future work includes selecting appropriate validated measures to assess each outcome domain.
Learn More >The A3 adenosine receptor (A3AR) has emerged as a therapeutic target with A3AR agonists to tackle the global challenge of neuropathic pain; investigation into their mode of action is essential for ongoing clinical development. A3ARs on immune cells, and their activation during pathology, modulates cytokine release. Thus, immune cells as a cellular substrate for the pharmacological action of A3AR agonists is enticing but unknown. Studies herein discovered that RagKO mice lacking T- and B-cells are insensitive to the anti-allodynic effects of A3AR agonists versus wild-type (WT) mice. Similar findings were observed in interleukin-10 and interleukin-10 receptor knockout mice. Adoptive transfer of CD4+ T-cells (CD4+-T) from WT mice infiltrated the dorsal root ganglion (DRG) and restored A3AR agonist-mediated anti-allodynia in RagKO mice; CD4+-T from Adora3KO or Il10KO mice did not. Transfer of CD4+-T from WT, but not Il10KO, into Il10KO mice fully reinstated anti-allodynic effects of A3AR activation. Transfer of CD4+-T from WT, but not Il10KO, into Adora3KO mice fully reinstated anti-allodynic effects of A3AR activation. Notably, A3AR agonism reduced DRG neuron excitability when co-cultured with CD4+-T in an IL-10-dependent manner. A3AR actions on CD4+-T infiltrate in the DRG decreased phosphorylation of GluN2B-containing N-methyl-D-aspartate receptors at Tyr1472, a modification associated with regulating neuronal hypersensitivity. Our findings establish that activation of A3AR on CD4+-T cells to release of IL-10 is required and sufficient for A3AR agonists as therapeutics.
Learn More >Scalable delivery models of cognitive behavioral therapy for insomnia (CBT-I), an effective treatment, are needed for widespread implementation, particularly in rural and underserved populations lacking ready access to insomnia treatment.
Learn More >Migraine is highly prevalent and is the sixth leading cause worldwide for years lost to disability. Therapeutic options specifically targeting migraine are limited, and delta opioid receptor (DOP) agonists were recently identified as a promising pharmacotherapy. The mechanisms by which DOPs regulate migraine are currently unclear. Calcitonin gene- related peptide (CGRP) has been identified as an endogenous migraine trigger and plays a critical role in migraine initiation and susceptibility. The aim of this study was to determine the behavioral effects of DOP agonists on the development of chronic migraine-associated pain, and to investigate DOP co-expression with CGRP and CGRP receptor in the trigeminal system. Chronic migraine-associated pain was induced in mice through repeated intermittent injection of the known human migraine trigger, nitroglycerin. Chronic nitroglycerin resulted in severe chronic cephalic allodynia which was prevented with co-treatment of the DOP-selective agonist, SNC80. In addition, a corresponding increase in CGRP expression in the trigeminal ganglia and trigeminal nucleus caudalis was observed after chronic nitroglycerin, an augmentation that was blocked by SNC80. Moreover, DOP was also upregulated in these head pain-processing regions following the chronic migraine model. Immunohistochemical analysis of the trigeminal ganglia revealed co-expression of DOP with CGRP as well as with a primary component of the CGRP receptor, RAMP1. In the trigeminal nucleus caudalis, DOP was not co-expressed with CGRP but was highly co-expressed with RAMP1 and calcitonin receptor like receptor. These results suggest that DOP agonists inhibit migraine-associated pain by attenuating CGRP release and inhibiting pro-nociceptive signaling of the CGRP receptor.
Learn More >Pruritus is a common symptom of inflammatory skin conditions, including atopic dermatitis (AD). Although primary sensory neurons that transmit pruritic signals are well-cataloged, little is known about the neuronal alterations that occur as a result of skin disruption in AD. To address this question, we examined the molecular and behavioral consequences of challenging mice, which overexpress PAR2 in suprabasal keratinocytes, with serial topical application of the environmental allergen house dust mite (HDM). We monitored behavior and used RNA sequencing, qPCR, and in situ hybridization to evaluate gene expression in trigeminal ganglia (TG), before and after HDM. We found that neither nor wild-type (WT) mice exhibited spontaneous scratching, and pruritogen-induced acute scratching did not differ. In contrast, HDM exacerbated scratching in mice. Despite the absence of scratching in untreated mice, several TG genes in these mice were up-regulated compared to WT. HDM treatment of the mice enhanced up-regulation of this set of genes and induced additional genes, many within the subset of TG neurons that express TRPV1. The same set of genes was up-regulated in HDM-treated mice that did not scratch, but at lesser magnitude. Finally, we recorded comparable transcriptional changes in IL31Tg mice, demonstrating that a common genetic program is induced in two AD models. Taken together, we conclude that transcriptional changes that occur in primary sensory neurons in dermatitis-susceptible animals underlie a genetic priming that not only sensitizes the animal to chronic allergens but also contributes to pruritus in atopic skin disease.
Learn More >The term menstrual migraine refers to migraine that is associated with menstruation by more than chance, but it does not define pathophysiology. Menstrual migraine affects about 20-25% of female migraineurs in the general population, and 22-70% of patients presenting to headache clinics. In women diagnosed with menstrual migraine, perimenstrual migraine attacks are associated with substantially greater disability than their non-menstrual attacks. Loose interpretation of diagnostic criteria has led to conflicting results in studies on prevalence figures, clinical characteristics, and response to treatment. Importantly, clinical trials often do not distinguish between perimenstrual attacks in women diagnosed with menstrual migraine and attacks associated with menstruation by chance. Two pathophysiological mechanisms have been identified: oestrogen withdrawal and prostaglandin release. Although management strategies targeting these mechanisms might be effective, the evidence is not robust. Given how common and debilitating this distinct condition is, more research investment is needed to expand understanding of its pathophysiology and to develop more effective treatment strategies.
Learn More >In this issue of Neuron, Parker et al. discover neuronal plumes of glutamate release that initiate spreading depolarization, the electrophysiologic event underlying migraine. Mice with human migraine mutations express spontaneous and frequent plumes, which may explain the propensity to develop migraine attacks and the increased stroke risk in migraine-susceptible brains.
Learn More >Orthopedic injury can occur from a variety of causes including motor vehicle collision, battlefield injuries or even falls from standing. Persistent limb pain is common after orthopedic injury or surgery and presents a unique challenge, as the initiating event may result in polytrauma to bone, muscle, and peripheral nerves. It is imperative that we understand the tissue-specific and multicellular response to this unique type of injury in order to best develop targeted treatments that improve healing and regeneration. In this Mini Review we will first discuss current rodent models of orthopedic trauma/complex orthotrauma. In the second section, we will focus on bone-specific outcomes including imaging modalities, biomechanical testing and immunostaining for markers of bone healing/turnover. In the third section, we will discuss muscle-related pathology including outcome measures of fibrosis, muscle regeneration and tensile strength measurements. In the fourth section, we will discuss nervous system-related pathology including outcome measures of pain-like responses, both reflexive and non-reflexive. In all sections we will consider parallels between preclinical outcome measures and the functional and mechanistic findings of the human condition.
Learn More >Osteoarthritis is a prevalent, debilitating, and costly chronic disease for which recommended first-line treatment is underused.
Learn More >Determine the role of calcitonin-gene related peptide in promoting post-traumatic headache and dysregulation of central pain modulation induced by mild traumatic brain injury in mice.
Learn More >This study evaluated a battery of pain-stimulated, pain-depressed, and pain-independent behaviors for preclinical pharmacological assessment of candidate analgesics in mice. Intraperitoneal injection of dilute lactic acid (IP acid) served as an acute visceral noxious stimulus to produce four pain-related behaviors in male and female ICR mice: stimulation of (1) stretching and (2) facial grimace, and depression of (3) rearing and (4) nesting. Additionally, nesting and locomotion in the absence of the noxious stimulus were used to assess pain-independent drug effects. These six behaviors were used to compare effects of two mechanistically distinct but clinically-effective positive controls (ketoprofen and oxycodone), and two negative controls that are not clinically approved as analgesics but produce either general motor depression (diazepam) or motor stimulation (amphetamine). We predicted that analgesics would alleviate all IP acid effects at doses that did not alter pain-independent behaviors, whereas negative controls would not. Consistent with this prediction, ketoprofen (0.1-32 mg/kg) produced the expected analgesic profile, whereas oxycodone (0.32-3.2 mg/kg) alleviated all IP acid effects except depression of rearing at doses lower than those that altered pain-independent behaviors. For the negative controls, diazepam (1-10 mg/kg) failed to block IP acid-induced depression of either rearing or nesting, and only decreased IP acid-stimulated behaviors at doses that also decreased pain-independent behaviors. Amphetamine (0.32-3.2 mg/kg) alleviated all IP acid effects, but only at doses that also stimulated locomotion. These results support utility of this model as a framework to evaluate candidate-analgesic effects in a battery of complementary pain-stimulated, pain-depressed, and pain-independent behavioral endpoints. Preclinical assays of pain and analgesia often yield false-positive effects with candidate analgesics. This study used two positive-control analgesics (ketoprofen, oxycodone) and two active negative controls (diazepam, amphetamine) to validate a strategy for distinguishing analgesics from non-analgesics by profiling drug effects in a battery of complementary pain-stimulated, pain-depressed, and pain-independent behaviors in male and female mice.
Learn More >Enhanced signaling of the endocannabinoid system (eCB) through inhibition of the catabolic enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) has received increasing interest for development of candidate analgesics. This study compared effects of MAGL and FAAH inhibitors with effects of ∆9-tetrahydrocannabinol (THC) using a battery of pain-stimulated, pain-depressed, and pain-independent behaviors in male and female mice. Intraperitoneal injection of dilute lactic acid (IP acid) served as an acute visceral noxious stimulus to stimulate two behaviors (stretching, facial grimace) and depress two behaviors (rearing, nesting). Nesting and locomotion were also assessed in the absence of IP acid as pain-independent behaviors. THC and a spectrum of six eCB catabolic enzyme inhibitors ranging from MAGL- to FAAH-selective were assessed for effectiveness to alleviate pain-related behaviors at doses that did not alter pain-independent behaviors. The MAGL-selective inhibitor MJN110 produced the most effective antinociceptive profile, with 1.0 mg/kg alleviating IP acid effects on stretching, grimace, and nesting without altering pain-independent behaviors. MJN110 effects on IP acid-depressed nesting had a slow onset and long duration (40min to 6hr), were blocked by rimonabant, and tended to be greater in females. As inhibitors increased in FAAH-selectivity, antinociceptive effectiveness decreased. PF3845, the most FAAH-selective inhibitor, produced no antinociception up to doses that disrupted locomotion. THC decreased IP acid-stimulated stretching and grimace at doses that did not alter pain-independent behaviors; however, it did not alleviate IP acid-induced depression of rearing or nesting. These results support further consideration of MAGL-selective as candidate analgesics for acute inflammatory pain. This study characterized a spectrum of endocannabinoid (eCB) catabolic enzyme inhibitors ranging in selectivity from monoacylglycerol lipase- (MAGL-) selective to fatty acid amide hydrolase- (FAAH-) selective in a battery of pain-stimulated, pain-depressed, and pain-independent behaviors previously pharmacologically characterized in a companion paper. This battery provides a method for prioritizing candidate analgesics by effectiveness to alleviate pain-related behaviors at doses that do not alter pain-independent behaviors, with inclusion of pain-depressed behaviors increasing translational validity and decreasing susceptibility to motor-depressant false positives.
Learn More >Transcranial, non-invasive stimulation of the primary motor cortex (M1) has recently emerged to show promise in treating clinically refractory neuropathic pain. However, there is a major need for improving efficacy, reducing variability and understanding mechanisms. Rodent models hold promise in helping to overcome these obstacles. However, there still remains a major divide between clinical and preclinical studies with respect to stimulation programs, analysis of pain as a multidimensional sensory-affective-motivational state and lack of focus on chronic phases of established pain. Here, we employed direct transcranial M1 stimulation (M1 tDCS) either as a single 5-day block or recurring blocks of repetitive stimulation over early or chronic phases of peripherally-induced neuropathic pain in mice. We report that repeated blocks of stimulation reverse established neuropathic mechanical allodynia more strongly than a single 5-day regime and also suppress cold allodynia, aversive behavior and anxiety without adversely affecting motor function over a long period. Activity mapping revealed highly selective alterations in the posterior insula, periaqueductal gray subdivisions and superficial spinal laminae in reversal of mechanical allodynia. Our preclinical data reveal multimodal analgesia and improvement in quality of life by multiple blocks of M1 tDCS and uncover underlying brain networks, thus helping promote clinical translation.
Learn More >Neck pain is frequent in patients with migraine. Likewise, evidence for inflammatory processes in the trapezius muscles is accumulating. However, non-invasive and objectively assessable correlates are missing .
Learn More >For a long time, the capacity of the newborn infant to feel pain was denied. Today it is clear that the nociceptive system, even if still immature, is functional enough in the newborn infant to elicit pain responses. Unfortunately, pain is often present in the neonatal period, in particular in the case of premature infants which are subjected to a high number of painful procedures during care. These are accompanied by a variety of environmental stressors, which could impact the maturation of the nociceptive system. Therefore, the question of the long term consequences of early life stress is a critical question. Early stressful experience, both painful and non-painful, can imprint the nociceptive system and induce long term alteration in brain function and nociceptive behavior, often leading to an increase sensitivity and higher susceptibility to chronic pain. Different animal models have been developed to understand the mechanisms underlying the long term effects of different early life stressful procedures, including pain and maternal separation. This review will focus on the clinical and preclinical data about early life stress and its consequence on the nociceptive system.
Learn More >In this protocol, we provide step-by-step instructions for dissection and culture of primary murine dorsal root ganglia (DRG), which provide an opportunity to study the functional properties of peripheral sensory neurons . Further, we describe the analysis of neuropeptide release by ELISA as a possible downstream application. In addition, isolated DRGs can be used directly for immunofluorescence, flow cytometry, RNA sequencing or proteomic approaches, electrophysiology, and calcium imaging. For complete details on the use and execution of this protocol, please refer to Perner et al. (2020).
Learn More >Small extracellular vesicles (sEVs) derived from antigen-presenting cells such as macrophages can induce therapeutically relevant immune responses. Anti-inflammatory miRNAs are elevated in sEVs secreted by RAW 264.7 mouse macrophages after lipopolysaccharide (LPS) stimulation. We observed uptake of these sEVs by primary mouse cortical neurons, microglia and astrocytes followed by downregulation of proinflammatory miRNA target genes in recipient cells. Pre-treating primary microglia with these sEVs decreased pro-inflammatory gene expression. A single intrathecal injection of sEVs derived from LPS stimulated RAW 264.7 cells attenuated mechanical hyperalgesia in the complete Freund's adjuvant (CFA) mouse model of inflammatory pain and formalin induced acute pain. Importantly, sEVs did not alter the normal pain threshold in control mice. RNA sequencing of dorsal horn of the spinal cord showed sEVs-induced modulation of immune regulatory pathways. Further, a single prophylactic intrathecal injection of sEVs two weeks prior, attenuated CFA-induced pain hypersensitivity and was ineffective in formalin model. This indicates that prophylactic sEVs administration can be beneficial in attenuating chronic pain without impacting responses to the protective physiological and acute inflammatory pain. Prophylactic administration of sEVs could form the basis for a safe and novel vaccine-like therapy for chronic pain or as an adjuvant, potentially reducing the dose of drugs needed for pain relief.
Learn More >Chronic musculoskeletal (MSK) pain is disabling to individuals and burdensome to society. A relationship between telomere length and resilience was reported in individuals with consideration for chronic pain intensity. While chronic pain associates with brain changes, little is known regarding the neurobiological interface of resilience. In a group of individuals with chronic MSK pain, we examined the relationships between a previously investigated resilience index, clinical pain and functioning measures, and pain-related brain structures, with consideration for sex and ethnicity/race. A cross-sectional analysis of 166 non-Hispanic Black and non-Hispanic White adults, 45-85 years of age with pain ≥ 1 body site (s) over the past 3 months was completed. Measures of clinical pain and functioning, biobehavioral and psychosocial resilience, and structural MRI were completed. Our findings indicate higher levels of resilience associate with lower levels of clinical pain and functional limitations. Significant associations between resilience, ethnicity/race, and/or sex, and pain-related brain gray matter structure were demonstrated in the right amygdaloid complex, bilateral thalamus, and postcentral gyrus. Our findings provide compelling evidence that in order to decipher the neurobiological code of chronic pain and related protective factors, it will be important to improve how chronic pain is phenotyped; to include an equal representation of females in studies including analyses stratifying by sex, and to consider other sociodemographic factors.
Learn More >Multimodal treatment is recognized as the optimal paradigm for the management of chronic pain (CP). Careful balance between pharmacological and physical/psychological approaches is thus desirable but can be easily disrupted.
Learn More >Neuroactive substances released by activated microglia contribute to hyperexcitability of spinal dorsal horn neurons in many animal models of chronic pain. An important feedback loop mechanism is via release of fractalkine (CX3CL1) from primary afferent terminals and dorsal horn neurons and binding to CX3CR1 receptors on microglial cells. We studied the involvement of fractalkine signaling in latent and manifest spinal sensitization induced by two injections of nerve growth factor (NGF) into the lumbar multifidus muscle as a model for myofascial low back pain. Single dorsal horn neurons were recorded in vivo to study their receptive fields and spontaneous activity. Under intrathecal vehicle application, the two NGF injections led to an increased proportion of neurons responding to stimulation of deep tissues (41%), to receptive field expansion into the hind limb (15%), and to resting activity (53%). Blocking fractalkine signaling by continuous intrathecal administration of neutralizing antibodies completely prevented these signs of spinal sensitization to a similar extent as in a previous study with the microglia inhibitor minocycline. Reversely, fractalkine itself induced similar sensitization in a dose dependent manner (for 200 ng/ml: 45% deep tissue responses, 24% receptive field expansion, 45% resting activity) as repeated nociceptive stimulation by intramuscular NGF injections. A subsequent single NGF injection did not have an additive effect. Our data suggest that neuron to microglia signaling via the CX3CL1-CX3CR1 pathway is critically involved in the initiation of non-specific, myofascial low back pain through repetitive nociceptive stimuli.
Learn More >Mas-related G coupled receptors (Mrgprs) are a superfamily of receptors expressed in sensory neurons that are known to transmit somatic sensations from the skin to the central nervous system. Interestingly, Mrgprs have recently been implicated in sensory and motor functions of mucosal-associated neuronal circuits. The gastrointestinal and pulmonary tracts are constantly exposed to noxious stimuli. Therefore, it is likely that neuronal Mrgpr signaling pathways in mucosal tissues, akin to their family members expressed in the skin, might relay messages that alert the host when mucosal tissues are affected by damaging signals. Further, Mrgprs have been proposed to mediate the cross-talk between sensory neurons and immune cells that promotes host-protective functions at barrier sites. Although the mechanisms by which Mrgprs are activated in mucosal tissues are not completely understood, these exciting studies implicate Mrgprs as potential therapeutic targets for conditions affecting the intestinal and airway mucosa. This review will highlight the central role of Mrgpr signaling pathways in the regulation of homeostasis at mucosal tissues.
Learn More >For patients suffering with chronic neuropathic pain the need for suitable novel therapies is imperative. Over recent years a contributing factor for the lack of development of new analgesics for neuropathic pain has been the mismatch of primary neuropathic pain assessment endpoints in preclinical vs. clinical trials. Despite continuous forward translation failures across diverse mechanisms, reflexive quantitative sensory testing remains the primary assessment endpoint for neuropathic pain and analgesia in animals. Restricting preclinical evaluation of pain and analgesia to exclusively reflexive outcomes is over simplified and can be argued not clinically relevant due to the continued lack of forward translation and failures in the clinic. The key to developing new analgesic treatments for neuropathic pain therefore lies in the development of clinically relevant endpoints that can translate preclinical animal results to human clinical trials. In this review we discuss this mismatch of primary neuropathic pain assessment endpoints, together with clinical and preclinical evidence that supports how bidirectional research is helping to validate new clinically relevant neuropathic pain assessment endpoints. Ethological behavioral endpoints such as burrowing and facial grimacing and objective measures such as electroencephalography provide improved translatability potential together with currently used quantitative sensory testing endpoints. By tailoring objective and subjective measures of neuropathic pain the translatability of new medicines for patients suffering with neuropathic pain will hopefully be improved.
Learn More >Evidence suggests that blunted reward responsiveness may account for poor clinical outcomes in both opioid use disorder (OUD) and chronic pain. Understanding how individuals with OUD and comorbid chronic pain (OUD+CP) respond to rewards is, therefore, of clinical interest because it may reveal a potential point of behavioral intervention.
Learn More >To review the acute migraine clinical trial literature and provide a summary of the endpoints and outcomes used in such trials.
Learn More >Cancer diagnosis and treatment are drastic events for patients and their families. Besides psychological aspects of the disease, patients are often affected by severe side effects related to the cancer itself or as a result of therapeutic interventions. Particularly, chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of oral or intravenous chemotherapy. The disorder may require dose reduction of chemotherapy and is accompanied by multiple symptoms with long-term functional impairment affecting quality of life (QoL), e.g., sensory and functional deteriorations as well as severe pain. Although CIPN may reverse or improve after termination of the causative chemotherapy, approximately 30-40% of patients are faced with chronicity of the symptoms. Due to the advantages in cancer diagnosis and treatments, survival rates of cancer patients rise and CIPN may occur even more frequently in the future. In this review, we summarize current recommendations of leading national and international societies regarding prevention and treatment options in CIPN. A special focus will be placed on current evidence for topical treatment of CIPN with high-dose capsaicin. Finally, an algorithm for CIPN treatment in clinical practice is provided, including both pharmacologic and non-pharmacologic modalities based on the clinical presentation.
Learn More >This pilot trial examined the effects of a combined intervention of mindfulness meditation followed by aerobic walking exercise compared with a control condition in chronic low back pain patients. We hypothesized that meditation before exercise would reduce disability, pain, and anxiety by increasing mindfulness prior to physical activity compared with an audiobook control group.
Learn More >Research on placebo analgesia commonly focuses on the impact of information about direction (i.e. increase or decrease of pain) and magnitude of the expected analgesic effect whereas temporal aspects of expectations have received little attention so far. In a recent study using short-lasting, low-intensity stimuli we demonstrated that placebo analgesia onset is influenced by temporal information. Here, we investigate whether the same effect of temporal suggestions can be found in longer lasting, high-intensity pain in a Cold Pressor Test (CPT).
Learn More >Findings on the short- and long-term effectiveness of intensive interdisciplinary pain treatment (IIPT) for children with severe chronic functional pain are promising. However, a definitive appraisal of long-term effectiveness cannot be made due to a lack of comparison groups. The aim of the present study was to compare the health status of former patients with the health status of an age- and sex-matched comparison group from the community.
Learn More >Mas gene-related G protein-coupled receptors (MRGPRs) are a GPCR family responsive to various exogenous and endogenous agonists, playing a fundamental role in pain and itch sensation. The primate-specific family member MRGPRX2 and its murine orthologue MRGPRB2 are expressed by mast cells, mediating IgE-independent signaling and pseudo-allergic drug reactions.
Learn More >The COVID-19 outbreak has been a great challenge in the management of chronic pain patients. We have conducted a rapid scoping review to assess the impact of the pandemic (and the associated public health measures) on the health status and management practices of chronic pain patients in Spain. To this end, we performed a bibliographic search in LitCOVID and PubMed, and reviewed official websites and documents, and expert reports. The review showed that (1) the studies consistently indicate that the pandemic has had a very negative impact on the physical and psychological health of chronic pain patients; (2) there are scarce data on how the pandemic affected pain unit consultations and a lack of protocols to organize health care in the face of future waves of contagion, with little implementation of telehealth. We make proposals to improve management of chronic pain patients in pandemic situations, which should pivot around 3 axes: (1) a coordinated response of all the relevant stakeholders to define a future roadmap and research priorities, (2) a biopsychosocial approach in pain management, and (3) development and implementation of novel telemedicine solutions.
Learn More >In late 2019, a novel coronavirus SARS-CoV-2 (COVID-19) spread unchecked across the world's population. With tens of millions infected, the long-term consequences of COVID-19 infection will be a major health care focus for years after the contagion subsides. Most complications stem from direct viral invasion provoking an over-exuberant inflammatory response driven by innate immune cells and activation of the clotting cascade causing thrombosis. Injury to individual organs and their protective linings are frequent presentations in respiratory, cardiovascular, and neurological systems. Reviewing the historical context of postviral fatiguing symptoms seems relevant to understanding reports of uneven recoveries and persistent symptoms that are emerging as "long-haul COVID-19." The pandemic is also an unprecedented sociocultural event, transforming how people consider their health, gather in groups, and navigate their daily lives. The unprecedented sociocultural stresses of the pandemic will have an invisible, ubiquitous, and predictable impact on neurologic, endocrine, and immune functioning, even in people untouched by the virus. COVID-19 may also have a surprise or two in store, with unique clinical presentations and novel mechanisms of injury which are yet to clearly emerge. Although challenging and unfortunate, these times also represent a unique opportunity to start to unravel the physiology that underlie how viruses may trigger cancers, neurological disease, and postviral fatiguing syndromes.
Learn More >Pain neuroscience education (PNE) combined with cognition-targeted exercises is an effective treatment for people with chronic spinal pain (CSP). However, it is unclear as to why some patients benefit more from this treatment. We expect that patients with more pronounced maladaptive pain cognitions, such as kinesiophobia, might show poorer treatment responses.
Learn More >Symptoms that resemble allergic reactions, such as pruritus, flushing, and hypotension, are common side effects of therapeutic drugs. In a true allergic reaction, Immunoglobulin E (IgE) antibodies recognize the drug and trigger mediator release from mast cells through cross-linking of IgE receptors. However, many drugs can bypass this pathway and can activate mast cells directly through MRGPRX2, a G protein-coupled receptor that responds to a wide range of small molecules, peptides, and proteins that have little in common except for a net positive charge. This review will provide an overview of MRGPRX2, including its expression pattern, studies of its pharmacology, and its orthologs. It also will review evidence for MRGPRX2 activation by many drugs closely associated with these reactions.
Learn More >The contribution of bacterial infection to chronic low back pain and its treatment with antibiotics have generated considerable controversy in literature. If efficacious, antibiotics have the potential to transform the treatment of chronic low back pain in a significant subset of patients. Some microbiology studies of disc tissue from patients with CLBP have shown that bacteria are present, most likely due to infection, while others conclude they are absent or if found, it is due to surgical contamination. Clinical studies testing the efficacy of oral antibiotics to treat CLBP have either shown that the treatment is efficacious leading to significantly reduced pain and disability or that their effect is modest and not clinically significant. Critical review of the literature on CLBP, bacterial infection and treatment with antibiotics identified five well-designed and executed microbiology studies characterising bacteria in disc samples that demonstrate that bacteria do infect herniated disc tissue, but that the bacterial burden is low and may be below the limits of detection in some studies. Two randomised, controlled clinical trials evaluating oral antibiotics in patients with CLBP indicate that for certain subsets of patients, the reduction in pain and disability achieved with antibiotic therapy may be significant. In patients for whom other therapies have failed, and who might otherwise progress to disc replacement or fusion surgery, antibiotic therapy may well be an attractive option to reduce the individual suffering associated with this debilitating condition. Additional clinical research is recommended to refine the selection of patients with CLBP caused or complicated by bacterial infection and most likely to respond to antibiotics, to optimise antibiotic therapy to maximise patient benefit, to minimise and manage side effects, and to address legitimate concerns about antibiotic stewardship.
Learn More >While the prevalence of radiographic and symptomatic osteoarthritis (OA) is higher in women, male mice are more frequently used in animal experiments to explore its pathogenesis or drug efficacy. In this study, we examined whether sexual dimorphism affects pain and joint degeneration in destabilization of the medial meniscus (DMM) mouse model.
Learn More >Over the past 50 years, ketamine has solidified its position in both human and veterinary medicine as an important anesthetic with many uses. More recently, ketamine has been studied and used for several new indications, ranging from chronic pain to drug addiction and post-traumatic stress disorder. The discovery of the rapid-acting antidepressant effects of ketamine has resulted in a surge of interest towards understanding the precise mechanisms driving its effects. Indeed, ketamine may have had the largest impact for advancements in the research and treatment of psychiatric disorders in the past few decades. While intense research efforts have been aimed towards uncovering the molecular targets underlying ketamine's effects in treating depression, the underlying neurobiological mechanisms remain elusive. These efforts are made more difficult by ketamine's complex dose-dependent effects on molecular mechanisms, multiple pharmacologically active metabolites, and a mechanism of action associated with the facilitation of synaptic plasticity. This review aims to provide a brief overview of the different uses of ketamine, with an emphasis on examining ketamine's rapid antidepressant effects spanning molecular, cellular, and network levels. Another focus of the review is to offer a perspective on studies related to the different doses of ketamine used in antidepressant research. Finally, the review discusses some of the latest hypotheses concerning ketamine's action.
Learn More >The Oxford Catalogue of Opioids: a systematic synthesis of opioid drug names and their pharmacology.
The growing demand for analgesia, coupled with an increasing need to treat opioid dependence and overdose, has escalated the development of novel opioids. We aimed to quantify the number of opioid drugs developed and to catalogue them based on their pharmacology.
Learn More >Metabolically Stable Neurotensin Analogs Exert Potent and Long-Acting Analgesia Without Hypothermia.
The endogenous tridecapeptide neurotensin (NT) has emerged as an important inhibitory modulator of pain transmission, exerting its analgesic action through the activation of the G protein-coupled receptors, NTS1 and NTS2. Whereas both NT receptors mediate the analgesic effects of NT, NTS1 activation also produces hypotension and hypothermia, which may represent obstacles for the development of new pain medications. In the present study, we implemented various chemical strategies to improve the metabolic stability of the biologically active fragment NT(8-13) and assessed their NTS1/NTS2 relative binding affinities. We then determined their ability to reduce the nociceptive behaviors in acute, tonic, and chronic pain models and to modulate blood pressure and body temperature. To this end, we synthesized a series of NT(8-13) analogs carrying a reduced amide bond at Lys-Lys and harboring site-selective modifications with unnatural amino acids, such as silaproline (Sip) and trimethylsilylalanine (TMSAla). Incorporation of Sip and TMSAla respectively in positions 10 and 13 of NT(8-13) combined with the Lys-Lys reduced amine bond (JMV5296) greatly prolonged the plasma half-life time over 20 hours. These modifications also led to a 25-fold peptide selectivity toward NTS2. More importantly, central delivery of JMV5296 was able to induce a strong antinociceptive effect in acute (tail-flick), tonic (formalin), and chronic inflammatory (CFA) pain models without inducing hypothermia. Altogether, these results demonstrate that the chemically-modified NT(8-13) analog JMV5296 exhibits a better therapeutic profile and may thus represent a promising avenue to guide the development of new stable NT agonists and improve pain management.
Learn More >This study aimed to explore the effects and possible mechanisms of intravenous lidocaine in postherpetic neuralgia (PHN) rats. Mechanical withdrawal thresholds and thermal withdrawal latencies were measured. Open field test, elevated plus maze test, and tail suspension test were used to assess anxiety- and depressive-like behaviors. Microglia and astrocytes in spinal dorsal horn (SDH), prefrontal cortex (PFC), anterior cingulate cortex (ACC), and hippocampus were analyzed. The expression of TNF-α, IL-1β, and IL-4 in SDH and serum were evaluated. Intravenous lidocaine alleviated mechanical allodynia and thermal hypoalgesia, downregulated the expression of TNF-α and IL-1β, and inhibited the activation of microglia and astrocytes in SDH. In addition, it reduced the activation of astrocyte but not microglia in PFC, ACC, and hippocampus. Intravenous lidocaine may relieve PHN by inhibiting the activation of microglia and astrocyte in SDH or by reducing the neuroinflammation and astrocyte activation in PFC, ACC, and hippocampus.
Learn More >Is Migraine Associated to Brain Anatomical Alterations? New Data and Coordinate-Based Meta-analysis.
A growing number of studies investigate brain anatomy in migraine using voxel- (VBM) and surface-based morphometry (SBM), as well as diffusion tensor imaging (DTI). The purpose of this article is to identify consistent patterns of anatomical alterations associated with migraine. First, 19 migraineurs without aura and 19 healthy participants were included in a brain imaging study. T1-weighted MRIs and DTI sequences were acquired and analyzed using VBM, SBM and tract-based spatial statistics. No significant alterations of gray matter (GM) volume, cortical thickness, cortical gyrification, sulcus depth and white-matter tract integrity could be observed. However, migraineurs displayed decreased white matter (WM) volume in the left superior longitudinal fasciculus. Second, a systematic review of the literature employing VBM, SBM and DTI was conducted to investigate brain anatomy in migraine. Meta-analysis was performed using Seed-based d Mapping via permutation of subject images (SDM-PSI) on GM volume, WM volume and cortical thickness data. Alterations of GM volume, WM volume, cortical thickness or white-matter tract integrity were reported in 72%, 50%, 56% and 33% of published studies respectively. Spatial distribution and direction of the disclosed effects were highly inconsistent across studies. The SDM-PSI analysis revealed neither significant decrease nor significant increase of GM volume, WM volume or cortical thickness in migraine. Overall there is to this day no strong evidence of specific brain anatomical alterations reliably associated to migraine. Possible explanations of this conflicting literature are discussed. Trial registration number: NCT02791997, registrated February 6th, 2015.
Learn More >The dorsal spinal cord contains projection neurons that transmit somatosensory information to the brain and interneurons which then modulate neuronal activity of these projection neurons and/or other interneurons. Interneurons can be subdivided into two groups: excitatory and inhibitory neurons. While inhibitory interneurons are thought to play a crucial role in analgesia, it is unclear whether they are involved in neuropathic pain. In the present study, we aimed to assess the proportion and neuronal activity of excitatory/inhibitory neurons in the dorsal spinal cord using a neuropathic pain model in rats. Following partial sciatic nerve ligation (PSNL), rats showed significant mechanical hyperalgesia, and subsequent immunohistochemical studies were conducted in laminae I-III of the dorsal spinal cord. We found that the number of FosB-immunoreactive cells was significantly higher; there was no change in the percentage of Pax2 positive/negative neurons in NeuN positive neurons; Pax2 negative neurons, but not Pax2 positive neurons, were predominantly activated in PSNL rats; and the immunofluorescence intensity of the calcium channel α2δ1 subunit was significantly higher. These results indicate that while peripheral nerve injury might not affect the proportion of excitatory and inhibitory neurons, it predominantly activates excitatory neurons in laminae I-III of the rat dorsal spinal cord.
Learn More >Over the last six decades (earliest included publication from 1959), clinical trials of migraine preventive treatments have led to the regulatory approval of many medications and devices. Despite similar clinical goals, the outcomes and endpoints used in these trials are broad and not well standardized.
Learn More >Pathogen infection triggers pain via activation of the innate immune system. Toll-like receptors (TLRs) and Nod-like receptors (NLRs) are the main components of innate immunity and have been implicated in pain signaling. We previously revealed that the TLR2-NLRP3-IL33 pathway mediates inflammatory pain responses during hyperactivity of innate immunity. However, their roles in neuropathic pain had remained unclear. Here we report that although knockout of TLR2 or NLRP3 does not affect spared nerve injury (SNI)-induced neuropathic pain, intrathecal inhibition of IL33/ST2 signaling with ST2 neutralizing antibodies reverses mechanical thresholds in SNI mice compared to PBS vehicle treated animals. This effect indicates a universal role of IL33 in both inflammatory and neuropathic pain states, and that targeting the IL33/ST2 axis could be a potential therapeutic approach for pain treatment.
Learn More >Decision aids can help inform appropriate selection of total knee replacement (TKR) for advanced knee osteoarthritis (OA). However, few decision aids combine patient education, preference assessment, and artificial intelligence (AI) using patient-reported outcome measurement data to generate personalized estimations of outcomes to augment shared decision-making (SDM).
Learn More >Symptomatic knee osteoarthritis (SKOA) is a chronic, disabling condition, requiring long-term pain management; over 800,000 SKOA patients in the USA use opioids chronically. We aim to characterize the societal economic burden of opioid use in this population.
Learn More >Opioid abuse is a chronic disorder likely involving stable neuroplastic modifications. While a number of molecules contributing to these changes have been identified, the broader spectrum of genes and gene networks that are affected by repeated opioid administration remain understudied.
Learn More >A sustained sensory stimulus with a periodic variation of intensity creates an electrophysiological brain response at associated frequencies, referred to as the steady-state evoked potential (SSEP). The SSEPs elicited by the periodic stimulation of nociceptors in the skin may represent activity of a brain network that is primarily involved in nociceptive processing. Exploring the behavior of this network could lead to valuable insights regarding the pathway from nociceptive stimulus to pain perception. We present a method to directly modulate the pulse rate of nociceptive afferents in the skin with a multisine waveform through intra-epidermal electric stimulation. The technique was demonstrated in healthy volunteers. Each subject was stimulated using a pulse sequence modulated by a multisine waveform of 3, 7 and 13 Hz. The EEG was analyzed for the presence of the base frequencies and associated (sub)harmonics. Topographies showed significant central and contralateral SSEP responses at 3, 7 and 13 Hz in respectively 7, 4 and 3 out of the 9 participants included for analysis. As such, we found that intra-epidermal stimulation with a multisine frequency modulated pulse sequence can generate nociceptive SSEPs. The possibility to stimulate the nociceptive system using multisine frequency modulated pulses offers novel opportunities to study the temporal dynamics of nociceptive processing.
Learn More >Non-headache literature inevitably influences headache research, but the way this interdisciplinary interaction occurs has seldom been evaluated.
Learn More >Chronic pain commonly occurs in people living with HIV (PLWH). Many PLWH in the United States obtain opioids for chronic pain management. Whether insomnia severity and depressive symptoms are exacerbated by chronic pain and opioid use in PLWH remains to be determined. This study examined insomnia severity and depressive symptoms in 85 PLWH with chronic pain and 35 PLWH without chronic pain. Among PLWH with chronic pain, reported opioid use was examined in relation to insomnia severity and depressive symptoms. PLWH with chronic pain reported significantly greater insomnia severity ( = .033) and depressive symptoms ( = .025) than PLWH without chronic pain. Among PLWH with chronic pain who reported opioid use ( = 36), insomnia severity was greater compared to those who denied opioid use ( = 49), even after controlling for pain severity and number of comorbidities ( = .026). Greater pain severity was significantly associated with greater insomnia severity ( < .001) and depressive symptoms ( = .048) among PLWH with chronic pain who reported opioid use. These associations were not significant among those PLWH with chronic pain who denied opioid use. Findings suggest that PLWH with chronic pain are likely to experience poor sleep and depressed mood. Furthermore, poor sleep was associated with opioid use among PLWH with chronic pain.
Learn More >To investigate between and within-woman differences in the association between menstruation and migraine days.
Learn More >VVZ-149 is a small molecule that both inhibits the glycine transporter type 2 and the serotonin receptor 5 hydroxytryptamine 2 A. In a randomized, parallel-group, and double-blind trial (NCT02844725), we investigated the analgesic efficacy and safety of VVZ-149 Injections, which is under clinical development as a single-use injectable product for treating moderate to severe postoperative pain.
Learn More >In dementia, neuropathological changes alter the perception and expression of pain. For clinicians and family members, this knowledge gap leads to difficulties in recognizing and assessing chronic pain, which may consequently result in persons with dementia receiving lower levels of pain medication compared to those without cognitive impairment. Although this situation seems to have improved in recent years, considerable geographical variation persists. Over the last decade, opioid use has received global attention as a result of overuse and the risk of addiction, while the literature on older persons with dementia actually suggests undertreatment. This review stresses the importance of reliable assessment and the regular evaluation and monitoring of symptoms in persons with dementia. Based on current evidence, we concluded that chronic pain is still undertreated in dementia.
Learn More >Pain is the prevailing symptom of knee osteoarthritis. Central sensitisation creates discordance between pain and joint pathology. We previously reported a central pain mechanisms trait derived from 8 discrete characteristics: neuropathic-like pain, fatigue, cognitive-impact, catastrophising, anxiety, sleep disturbance, depression, and pain distribution. We here validate and show that an 8-item questionnaire, Central Aspects of Pain in the Knee (CAP-Knee) is associated both with sensory and affective components of knee pain severity.
Learn More >The analysis of brain signal variability is a promising approach to understand pathological brain function related to chronic pain. This study investigates whether blood-oxygen-level-dependent signal variability (BOLD) in specific frequency bands is altered in temporomandibular disorder (TMD) and correlated to its clinical features. Twelve patients with chronic myofascial TMD and 24 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging. The BOLD was measured as the standard deviation of the BOLD time series at each voxel and compared between groups. We also examined the potential relationship between the BOLD and the catechol–methyltransferase () ValMet polymorphism. We assessed sensory-discriminative pain in the craniofacial region, pain sensitivity to sustained masseteric pain challenge, and TMD pain frequency for clinical correlation. Patients displayed reduced BOLD in the dorsolateral prefrontal cortex (dlPFC) as compared with HC in all frequency bands. In the slow-3 band, patients also showed reduced BOLD in the medial dorsal thalamus, primary motor cortex (M1), and primary somatosensory cortex (S1) and heightened BOLD in the temporal pole. Notably, we found a significant correlation between lower BOLD (slow-3) in the orofacial M1/S1 regions and higher clinical pain (intensity/area) and higher sensitivity of the masseter muscle pain. Moreover, lower BOLD (slow-3) in the dlPFC and ventrolateral PFC was associated with a higher TMD pain frequency. Participants who had the Met substitution exhibited lower BOLD in the dlPFC and higher BOLD in the temporal pole as compared with participants without the Met substitution. An increasing number of Met alleles was associated with lower dlPFC and greater temporal pole BOLD in both HC and TMD groups. Together, we demonstrated that chronic TMD patients exhibit aberrant BOLD in the top-down pain modulatory and sensorimotor circuits associated with their pain frequency and severity. ValMet polymorphism might affect clinical symptoms in association with regional brain signal variability, specifically involved in cognitive and emotional regulation of pain.
Learn More >Extracellular vesicles (EVs) are capable of transferring microRNAs (miRNAs or miRs) between two different types of cells and also serve as vehicles for delivery of therapeutic molecules. After peripheral nerve injury, abnormal expression patterns of miRNAs have been observed in dorsal root ganglia (DRG) sensory neurons. We hypothesized that sensory neurons secrete miRs-containing EVs to communicate with macrophages. We demonstrated that miR-23a was upregulated in DRG neurons in spared nerve injury (SNI) mouse models. We also found that miR-23a was enriched in EVs released by cultured DRG neurons following capsaicin treatment. miR-23a-containing EVs were taken up into macrophages in which increased intracellular miR-23a promoted pro-inflammatory phenotype. A20 was verified as a target gene of miR-23a. Moreover, intrathecal delivery of EVs-miR-23a antagomir attenuated neuropathic hypersensitivity and reduced the number of M1 macrophages in injured DRGs by targeting A20. In conclusion, these results demonstrate that sensory neurons transfer EVs-encapsulated miR-23a to activate M1 macrophages and enhance neuropathic pain following the peripheral nerve injury. The study highlighted a new therapeutic approach to alleviate chronic neuropathic pain after nerve trauma by targeting detrimental miRNA in sensory neurons.
Learn More >Neuropathic pain is a complex condition characterized by sensory, cognitive and affective symptoms that magnify the perception of pain. The underlying pathogenic mechanisms are largely unknown and there is an urgent need for the development of novel medications. The endocannabinoid system modulates pain perception and drugs targeting the cannabinoid receptor type 2 (CB2) devoid of psychoactive side effects could emerge as novel analgesics. An interesting model to evaluate the mechanisms underlying resistance to pain is the fragile X mental retardation protein knockout mouse (Fmr1KO), a model of fragile X syndrome that exhibits nociceptive deficits and fails to develop neuropathic pain.
Learn More >The experience of pain is a complex interaction of somatic, behavioral, affective, and cognitive components. Negative psychological states (e.g., anxiety, fear, and depression) are intertwined with pain and contribute to poorer outcomes for individuals suffering from chronic and acute pain by exacerbating the overall experience of pain and leading to increased dysfunction, disability, and distress. A need exists for efficient assessment of aversive emotional states that are associated with pain.
Learn More >Juvenile-onset fibromyalgia (JFM) is a chronic debilitating pain condition that negatively impacts physical, social and academic functioning. Cognitive-behavioral therapy (CBT) is beneficial in reducing functional disability among adolescents with JFM but has only a modest impact on pain reduction and does not improve physical exercise participation. This randomized controlled trial (RCT) aims to test whether a novel intervention that combines CBT with specialized neuromuscular exercise training (the Fibromyalgia Integrative Training program for Teens "FIT Teens") is superior to CBT alone or a graded aerobic exercise (GAE) program.
Learn More >Despite the success of combined antiretroviral therapy (cART) in reducing viral load, a substantial portion of Human Immunodeficiency Virus (HIV)+ patients report chronic pain. The exact mechanism underlying this co-morbidity even with undetectable viral load remains unknown, but the transactivator of transcription (HIV-Tat) protein is of particular interest. Functional HIV-Tat protein is observed even in cerebrospinal fluid of patients who have an undetectable viral load. It is hypothesized that Tat protein exposure is sufficient to induce neuropathic pain-like manifestations via both activation of microglia and generation of oxidative stress. iTat mice conditionally expressed Tat protein in the central nervous system upon daily administration of doxycycline (100 mg/kg/d, i.p., up to 14 days). The effect of HIV-Tat protein exposure on the well-being of the animal was assessed using sucrose-evoked grooming and acute nesting behavior for pain-depressed behaviors, and the development of hyperalgesia assessed with warm-water tail-withdrawal and von Frey assays for thermal hyperalgesia and mechanical allodynia, respectively. Tissue harvested at select time points was used to assess ex vivo alterations in oxidative stress, astrocytosis and microgliosis, and blood-brain barrier integrity with assays utilizing fluorescence-based indicators. Tat protein induced mild thermal hyperalgesia but robust mechanical allodynia starting after 4 days of exposure, reaching a nadir after 7 days. Changes in nociceptive processing were associated with reduced sucrose-evoked grooming behavior without altering acute nesting behavior, and in spinal cord dysregulated free radical generation as measured by DCF fluorescence intensity, altered immunohistochemical expression of the gliotic markers, Iba-1 and GFAP, and increased permeability of the blood-brain barrier to the small molecule fluorescent tracer, sodium fluorescein, in a time-dependent manner. Pretreatment with the anti-inflammatory, indomethacin (1 mg/kg/d, i.p.), the antioxidant, methylsulfonylmethane (100 mg/kg/d i.p.), or the immunomodulatory agent, dimethylfumarate (100 mg/kg/d p.o.) thirty minutes prior to daily injections of doxycycline (100 mg/kg/d i.p.) over 7 days significantly attenuated the development of Tat-induced mechanical allodynia. Collectively, the data suggests that even acute exposure to HIV-1 Tat protein at pathologically relevant levels is sufficient to produce select neurophysiological and behavioral manifestations of chronic pain consistent with that reported by HIV-positive patients.
Learn More >Chronic opioid use is unfortunately perceived among these postoperative patients, specifically within orthopedic surgery. Patients having orthopedic surgeries are at risk for becoming addicted to opioids, and one benefit of peripheral nerves blocks could be to provide an alternative mode of pain control. This study takes a retrospective look at the use of peripheral nerve blocks for pain control following surgery for isolated traumatic ankle injuries. We hypothesize that when peripheral nerve blocks are administered preoperatively to patients with closed ankle fractures, they will have overall better control of postoperative pain compared to patients who did not receive a peripheral nerve block.
Learn More >Animal studies have shown that high-frequency stimulation (HFS) of peripheral C-fibres induces long-term potentiation (LTP) within spinal nociceptive pathways. The aim of this replication study was to assess if a perceptual correlate of LTP can be observed in humans. In 20 healthy volunteers, we applied HFS to the left or right volar forearm. Before and after applying HFS, we delivered single electrical test stimuli through the HFS electrode while a second electrode at the contra-lateral arm served as a control condition. Moreover, to test the efficacy of the HFS protocol, we quantified changes in mechanical pinprick sensitivity before and after HFS of the skin surrounding both electrodes. The perceived intensity was collected for both electrical and mechanical stimuli. After HFS, the perceived pain intensity elicited by the mechanical pinprick stimuli applied on the skin surrounding the HFS-treated site was significantly higher compared to control site (heterotopic effect). Furthermore, we found a higher perceived pain intensity for single electrical stimuli delivered to the HFS-treated site compared to the control site (homotopic effect). Whether the homotopic effect reflects a perceptual correlate of homosynaptic LTP remains to be elucidated.
Learn More >Dry needling is a treatment technique used by clinicians to relieve symptoms in patients with tension-type headache (TTH), cervicogenic headache (CGH), or migraine. This systematic review's main objective was to assess the effectiveness of dry needling on headache pain intensity and related-disability in patients with TTH, CGH, or migraine.
Learn More >The aim of this article was to provide an overview of adverse events reported for erenumab in post-marketing through the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and perform a disproportionality analysis with other drugs used for acute or preventative treatment of migraine as controls.
Learn More >Sleep problems are common among chronic pain patients who take opioids. There are documented effects of opioids on sleep architecture; however, the long-term effects of opioids on sleep remain unknown. This study examined whether opioid-naïve participants have better sleep quality than current and previous chronic users of opioids. We also explored whether sleep differed between methadone and buprenorphine users, and whether amount of time since abstaining from opioids was associated with sleep quality.
Learn More >Ubrogepant is an oral, small-molecule calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine. The efficacy and safety of ubrogepant were demonstrated in two pivotal phase 3, single-attack, randomized, placebo-controlled trials (ACHIEVE I and ACHIEVE II).
Learn More >Insomnia has been linked to acute and chronic pain conditions; however, it is unclear whether such relationships are causal. Recently, a large number of genetic variants have been discovered for both insomnia and pain through genome-wide association studies (GWAS) providing a unique opportunity to examine evidence for causal relationships through the use of the Mendelian randomization paradigm.
Learn More >Prescription opioids are powerful pain-controlling medications that have both benefits and potentially serious risks. Morphine is one of the preferred analgesics that are widely used to treat chronic pain. However, chronic morphine exposure has been found to cause both functional and structural changes in several brain regions, including the medial prefrontal cortex (mPFC), ventral tegmental area (VTA), and hippocampus (HPC), which lead to addictive behavior. Caveolin-1 (Cav-1), a scaffolding protein of membrane lipid rafts (MLRs), has been shown to organize GPCRs and multiple synaptic signaling proteins within the MLRs to regulate synaptic signaling and neuroplasticity. Previously, we showed that in vitro morphine treatment significantly elevates Cav-1 expression and causes neuroplasticity changes. In this study, we confirmed that chronic morphine exposure can significantly increase Cav-1 expression (P < 0.05) and microtubule-associated protein (MAP-2)-positive neuronal dendritic growth in the hippocampus. Moreover, the rewarding effect and dendritic growth in the HPC induced by chronic morphine exposure were significantly inhibited by hippocampal Cav-1 knockdown. Together, these data suggest that Cav-1 in the hippocampus plays an essential role in the neuroplasticity changes that underlie morphine addiction behaviors.
Learn More >Supratentorial sensory perception, including pain, is subserved by the trigeminal nerve, in particular, by the branches of its ophthalmic division, which provide an extensive innervation of the dura mater and of the major brain blood vessels. In addition, contrary to previous assumptions, studies on awake patients during surgery have demonstrated that the mechanical stimulation of the pia mater and small cerebral vessels can also produce pain. The trigeminovascular system, located at the interface between the nervous and vascular systems, is therefore perfectly positioned to detect sensory inputs and influence blood flow regulation. Despite the fact that it remains only partially understood, the trigeminovascular system is most probably involved in several pathologies, including very frequent ones such as migraine, or other severe conditions, such as subarachnoid haemorrhage. The incomplete knowledge about the exact roles of the trigeminal system in headache, blood flow regulation, blood barrier permeability and trigemino-cardiac reflex warrants for an increased investigation of the anatomy and physiology of the trigeminal system. This translational review aims at presenting comprehensive information about the dural and brain afferents of the trigeminovascular system, in order to improve the understanding of trigeminal cranial sensory perception and to spark a new field of exploration for headache and other brain diseases.
Learn More >The purpose of this study was to investigate the utility of data-driven analyses of functional magnetic resonance imaging (fMRI) data, by means of structural equation modeling, for the investigation of pain processing in fibromyalgia (FM).
Learn More >Fibromyalgia is a chronic condition characterised by widespread musculoskeletal pain. Although accumulating evidence suggests that exposure to stressful events increases the risk for this complex disorder, this is the first meta-analysis to compare the impact of a full range of lifetime stressors (e.g. physical trauma through to emotional neglect) on adult fibromyalgia.
Learn More >There is a lack of data on the burden of primary headache disorders such as migraine on emergency services. Existing data relies on a coding of "headache", which encompasses both primary and secondary headache of all causes; for example, subarachnoid haemorrhage. Guy's and St Thomas' NHS Trust in London is one of the UK's busiest emergency departments with 150,000 attendances per year. Our aim was to assess the healthcare resource utilisation of primary headaches, in particular migraine, in acute medical services.
Learn More >Interplay between physiological systems in the body plays a prominent role in health and disease. At the cellular level, such interplay is orchestrated through the binding of specific ligands to their receptors expressed on cell surface. G protein-coupled receptors (GPCR) are seven-transmembrane domain receptors that initiate various cellular responses and regulate homeostasis. In this review, we focus on particular GPCRs named Mas-related G protein-coupled receptors (Mrgprs) mainly expressed by sensory neurons and specialized immune cells. We describe the different subfamilies of Mrgprs and their specific ligands, as well as recent advances in the field that illustrate the role played by these receptors in neuro-immune biological processes, including itch, pain and inflammation in diverse organs.
Learn More >G protein-coupled receptor kinase 6 (GRK6) is part of the G protein-coupled receptor kinase family, whose members act as key regulators of seven-transmembrane receptor signalling. GRK6 seems to play a role in regulation of inflammatory processes, but mechanisms of transcriptional regulation of GRK6 expression in inflammatory cell lines have not been characterized. Protein kinase C (PKC) signalling is also involved in inflammatory regulation and an impact of PKC activation on GRK6 protein expression was described previously. Thus, the aim of this study was to 1) characterize the GRK6 promoter, and 2) investigate a potential influence of PKC on GRK6 expression.
Learn More >The purpose of this study was to evaluate the subsequent health resource utilization (HRU) between patients with migraine who received opioid medications at their emergency department (ED) visits ("opioid recipients") versus patients with migraine who did not receive opioid medications at their ED visits ("non-recipients").
Learn More >Electroconvulsive therapy (ECT) has been applied for chronic pain for decades. The amounts of opioids to treat pain are sometimes reduced after a series of ECT. The effect of ECT on morphine-induced analgesia and its mechanism underlying the reduction of morphine requirement has yet to be clarified. Therefore, we administered electroconvulsive shocks (ECS) to mice and investigated the antinociceptive effect of morphine in a hot plate test. We examined the expression level of µ-opioid receptor in the thalami of mice 25 h after administration of ECS compared to the thalami of mice without ECS administration using western blotting. ECS disturbed the development of a decrease in the percentage of maximal possible effect (%MPE), which was observed 24 h after a morphine injection, when ECS was applied 25, 23, 21, and 12 h before the second administration of morphine. We also examined the effect of ECS on the dose-response curve of %MPE to morphine-antinociception. Twenty-five hours after ECS, the dose-response curve was shifted to the left, and the EC of morphine given to ECS-pretreated mice decreased by 30.1% compared to the mice that were not pretreated with ECS. We also found that the expression level of µ-opioid receptors was significantly increased after ECS administration. These results confirm previous clinical reports showing that ECT decreased the required dose of opioids in neuropathic pain patients and suggest the hypothesis that this effect of ECT works through the thalamus.
Learn More >First-line pharmacotherapy for neuropathic pain entails the use of systemic antidepressants and anticonvulsants. These drugs are not optimally effective and poorly tolerated, especially for older patients with comorbid conditions. Given the high number of such patients, there is a need for a greater repertoire of safer and more effective analgesics. Clonidine and pentoxifylline are vasodilator agents that work synergistically to enhance tissue perfusion and oxygenation. The topical administration of these drugs, individually and in combination, has shown anti-nociceptive properties in rodent models of neuropathic pain. A topically-administered combination of clonidine and pentoxifylline also effectively reduced the intensity of both spontaneous and evoked pain in healthy volunteers with experimentally-induced neuropathic pain. The next step in advancing this formulation to clinical use is the undertaking of a phase II clinical study to assess its efficacy and safety in neuropathic pain patients.
Learn More >This systematic review and meta-analysis examined relationships between low back pain (LBP)-related disability and pain beliefs, including pain catastrophizing, pain-related fear, self-efficacy, and back pain beliefs, in non-English-speaking populations. Additionally, the effects of selected cultural factors (i.e., language/geographic area) on the strength of relationships were examined.
Learn More >To use the phenotyping data from the MAPP-II Symptom Patterns Study (SPS) to compare the systemic features between urologic chronic pelvic pain syndrome (UCPPS) with Hunner lesion (HL) versus those without HL.
Learn More >Recent studies indicated that analgesic overuse upregulated 5-hydroxytryptamine receptor 2A (5-HTR) and subsequently activated nitric oxide synthase (NOS) and thus induced latent sensitization, which provided a mechanistic basis for medication-overuse headache (MOH). Moreover, glycogen synthase kinase-3β (GSK-3β) was regulated by serotonin receptors and the phosphorylation of GSK-3β affected NOS activity, indicating that GSK-3β could be involved in the regulation of NOS activity by 5-HTR in MOH pathophysiology. Herein, we performed this study to investigate the role of 5-HTR in MOH pathophysiology and the role of GSK-3β in the regulation of NOS activity by 5-HTR.
Learn More >Although evidence-based psychological interventions improve chronic pain, many patients do not engage in behavioral health services. Offering a brief intervention in a medical setting may provide benefits to patients with chronic pain. The purpose of this study was to examine preliminary outcomes of a brief psychological intervention for chronic pain delivered in primary care.
Learn More >Several randomized controlled trials have implemented cognitive behavioral therapy for insomnia (CBT-I) for patients with comorbid insomnia and chronic pain. This systematic review and meta-analysis investigated the effectiveness of CBT-I on patient-reported sleep, pain, and other health outcomes (depressive symptoms, anxiety symptoms, and fatigue) in patients with comorbid insomnia and chronic non-cancer pain. A systematic literature search was conducted using eight electronic databases. Upon duplicate removal, 6374 records were screened against the inclusion criteria. Fourteen randomized controlled trials were selected for the review, with twelve (N = 762 participants) included in the meta-analysis. At post-treatment, significant treatment effects were found on global measures of sleep (standardized mean difference = 0.89), pain (0.20), and depressive symptoms (0.44). At follow-up (up to 12 mo), CBT-I significantly improved sleep (0.56). Using global measures of sleep, we found a probability of 81% and 71% for having better sleep after CBT-I at post-treatment and final follow-up, respectively. The probability of having less pain after CBT-I at post-treatment and final follow-up was 58% and 57%, respectively. There were no statistically significant effects on anxiety symptoms and fatigue at either assessment point. Future trials with sufficient power, longer follow-up periods, and inclusion of CBT for pain components are warranted.
Learn More >Sensory nerves regulate cutaneous local inflammation indirectly through induction of pruritus and directly by acting upon local immune cells. The underlying mechanisms for how sensory nerves influence cutaneous acquired immune responses remain to be clarified.
Learn More >Herpes zoster (HZ) is caused by reactivation of latent varicella zoster virus (VZV) in the cranial nerve or dorsal root ganglia, with spread of the virus along the sensory nerve to the dermatome. Postherpetic neuralgia is a feared complication of HZ and impairs patients' quality of life enormously. However, there is no predictor of the duration of neuralgia. Our objective was to investigate whether there are correlations between the duration of neuralgia and serum levels of potential biomarkers in order to find practical predictors of the duration of neuralgia. Patients who were diagnosed with HZ at our hospital from April 2013 to January 2014 were included in this study. Serum levels of cytokines and other biomarkers were measured using commercial enzyme-linked immunosorbent assay kits. Thirty patients (15 men and 15 women) with HZ were enrolled in this study. The mean age was 66.1 ± 9.2 (standard deviation) years (range, 51-84 years). Four patients were evaluated as having mild, 19 as having moderate, and seven as having severe HZ. Patients with severe HZ suffered from neuralgia for a significantly longer period of time than patients with mild-to-moderate HZ (9.86 ± 8.25 months vs. 2.01 ± 2.68 months, severe vs. mild-to-moderate, p = 0.0021). The serum interleukin (IL)-10 level was significantly higher in patients with severe HZ than in those with mild-to-moderate HZ (12.93 ± 3.27 pg/mL vs. 6.74 ± 3.72 pg/mL; severe vs. mild-to-moderate; p = 0.0487). Furthermore, the serum IL-10 level was significantly correlated with the duration of neuralgia (r = 0.5193, p = 0.0111). Lastly, the serum IL-10 level significantly decreased after treatment in comparison with that before treatment (from 8.15 ± 4.46 pg/mL to 4.32 ± 11.83 pg/mL, p < 0.0001). In conclusion, these results suggest that the serum IL-10 level is an objective biomarker of the severity of HZ, and that the serum IL-10 level can be a practical predictor of the duration of neuralgia.
Learn More >Paclitaxel is a widely prescribed chemotherapy drug for treating solid tumors. However, paclitaxel-induced peripheral neuropathy (PIPN) is a common adverse effect during paclitaxel treatment, which results in sensory abnormalities and neuropathic pain among patients. Unfortunately, the mechanisms underlying PIPN still remain poorly understood. Long noncoding RNAs (lncRNAs) are novel and promising targets for chronic pain treatment, but their involvement in PIPN still remains unexplored.
Learn More >The multimorbidity formed by sleep disturbances and pain conditions is highly prevalent and has a significant impact in global health and in the socioeconomic system. Although different approaches have been directed toward its management, evidence regarding an optimal treatment is lacking, and pharmacological options are often preferred. Health professionals (e.g., pain and sleep clinicians) tend to focus on their respective expertise, targeting a single symptom with a single drug. This may increase polypharmacy and the risk of drug interactions, adverse events, and mortality. Hence, the use of medications that can directly or indirectly improve sleep, pain, and other possible accompanying conditions without exacerbating them becomes especially relevant. The objectives of this comprehensive review are to: a) describe the beneficial or deleterious effects that some commonly used medications to manage pain have on sleep and sleep disorders; and b) describe the beneficial or deleterious effects that frequently prescribed medications for sleep may have on pain. Moreover, medications targeting some specific sleep-pain interactions will be suggested and future directions for improving sleep and alleviating pain of these patients will be provided with clinical and research perspectives.
Learn More >Lumbar spinal canal stenosis (LSS) or mechanical compression of dorsal root ganglion (DRG) is one of the causes of low back pain and neuropathic pain (NP). Lysophosphatidic acid (LPA) is a potent bioactive lipid mediator that is produced mainly from lysophosphatidylcholine (LPC) via autotaxin (ATX) and is known to induce NP via LPA receptor signaling in mice. Recently, we demonstrated that LPC and LPA were higher in cerebrospinal fluid (CSF) of patients with LSS. Based on the possible potential efficacy of the ATX inhibitor for NP treatment, we used an NP model with compression of DRG (CD model) and investigated LPA dynamics and whether ATX inhibition could ameliorate NP symptoms, using an orally available ATX inhibitor (ONO-8430506) at a dose of 30 mg/kg. In CD model, we observed increased LPC and LPA levels in CSF, and decreased threshold of the pain which were ameliorated by oral administration of the ATX inhibitor with decreased microglia and astrocyte populations at the site of the spinal dorsal horn projecting from injured DRG. These results suggested possible efficacy of ATX inhibitor for the treatment of NP caused by spinal nerve root compression and involvement of the ATX-LPA axis in the mechanism of NP induction.
Learn More >Accumulating evidence indicates that the brain natriuretic peptide(BNP) and its receptor (natriuretic peptide receptor, NPR) are widely distributed in a variety of tissues including trigeminal ganglion (TG). Furthermore, recent studies support the involvement of the BNP-NPRA pathway in acute and chronic pain. To investigate the role of this pathway in chronic pain, an infraorbital nerve-chronic constriction injury (ION-CCI) model of trigeminal neuralgia (TN) was produced in the rat. The time-course of changes in mechanical pain threshold was examined. We observed an upregulation of BNP and NPR-A and a downregulation of BKCa mRNA and protein in rats subjected to ION-CCI. Patch clamping experiments in vitro found that BKCa currents were significantly reduced in rats subjected to ION-CCI. BNP increased BKCa currents in ION-CCI rats. These results suggest that BNP and NPRA might serve as endogenous pain relievers in ION-CCI rats. Modulation of the BNP/NPR-A/BKCa channel pathway in TG may be a viable strategy for the treatment of TN.
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